Amina Bensalem1, Reynald Magnier1, Claudine Zemirline1, Evelyne Coussanes1, Pierre-Louis Toutain2 .
1Ceva Santé Animale, Libourne, France. 2Royal Veterinary College, University of London, London, United Kingdom.
Objectives:
Dapagliflozin is approved for human patients with diabetes, cardiac and renal disease. Daily dose of dapagliflozin capable of inducing 75% of the maximum 24-hour urinary glucose excretion (24h-UGE) has previously been shown to be predictive of clinical cardio-renal efficacy in human [1]. However, no PK–PD study of dapagliflozin in dogs is available. The objectives of this study were to investigate the pharmacokinetics of dapagliflozin, and the relationship between dapagliflozin concentrations and 24h-UGE in healthy dogs to compute an effective dosage of dapagliflozin in the treatment of different altered conditions in dogs.
Methods:
In this study, 12 male healthy Beagle dogs were assessed. The study was carried out over 4 periods of 7 days each with a two-week washout between each period. Dogs remained untreated in period 1. During the other three periods, dogs received dapagliflozin orally as tablets once daily for the first 5 consecutive days of each period. The order of magnitude of dosages to be tested for this trial were estimated using an allometric approach based on the respective clearances in humans and dogs, which provided a dose of about 0.1 mg/kg/day in dogs. The doses tested in the study according to a 4-periods sequential design were: 0 (control), 0.125, 0.5 and 2 mg/kg/day. Plasma concentrations of dapagliflozin were measured 9 and 12 times, respectively, after administration of the first and last dose of each treatment period, and 2 times between days 2 and 4 of each treatment period. Urine was collected three times daily after each administration, and glucose concentration was measured. The 24h-UGE was used as a pharmacodynamic endpoint to assess dapagliflozin efficacy. Pharmacokinetic and concentration-24h-UGE relationship analysis was performed using a nonlinear mixed-effects model with Monolix Suite 2021R1.
Results:
A two-compartment model with a first-order absorption rate constant and an absorption lag time best described pharmacokinetic data. A direct Emax PK-PD model well described the 24h-UGE data. Regarding the PK parameters, the estimated mean time to absorption was 0.05 h, apparent volume of distribution at equilibrium was 977 mL.kg-1, and the apparent plasma clearance (CL/F) was 74.65 mL.h-1.kg-1. Regarding the PD parameters, the estimated mean maximum glucose excretion in urine was 29.17 g.day-1, the 24h-dapagliflozin exposure to obtain half Emax (AUCtau50) was 759 ng.h.mL-1, and the 24h-exposure to obtain 75% of the maximum UGE response was 1139 ng.h.mL-1. The daily dose of dapagliflozin that induces 75% of the maximum 24h-UGE in healthy dogs was determined to be 0.10 mg/kg/day. Moreover, considering a variability of 30 % or 80 % in pharmacokinetic parameters (i.e. CL/F and AUCtau50) the oral dose of dapagliflozin that covers 99% of dogs was determined to be 0.22 mg/kg/day and 0.88 mg/kg/day, respectively.
Conclusions: This is the first study describing the pharmacokinetics (PK) and the concentration-effect relationship of oral dapagliflozin in healthy dogs using a population PK-PD modeling approach. The PK of dapagliflozin was well described using a two-compartment model with a first-order absorption rate constant and an absorption lag time; and the 24h-UGE was well described using a direct Emax PK-PD model. The oral daily dose of dapagliflozin that induces 75% of the maximum glucosuria in healthy dogs was determined to range between 0.10-0.88 mg/kg/day.
References:
[1] European public assessment reports. Forxiga, dapagliflozin. Procedure No. EMEA/H/C/002322 https://www.ema.europa.eu/en/documents/assessment-report/forxiga-epar-public-assessment-report_en.pdf
Reference: PAGE 32 (2024) Abstr 11048 [www.page-meeting.org/?abstract=11048]
Poster: Drug/Disease Modelling - Other Topics